Although the hemochromatosis gene (HFE) has been identified there is little information about the diabetes that often accompanies the disease. We hypothesize nondiabetic homozygotes for mutations in HFE will exhibit a defect in insulin secretion as iron overload develops. This notion is supported by preliminary data obtained in HFE mutant mice. The insulin deficiency will progress to type 2 diabetes only if insulin resistance also occurs, either from cirrhosis or inheritance of type 2 diabetes genes. Insulin resistance from cirrhosis is hypothesized to result from excess carbohydrate delivery to peripheral tissues, resulting in excess hexosamine generation, an established cause of insulin resistance. Our specific aims are to: 1. Determine the prevalence of impaired glucose intolerance (IGT) and diabetes in clinically unselected individuals with hemochromatosis by oral glucose tolerance criteria. 2. Determine if a defect in insulin secretion exists in nondiabetic homozygotes with or without iron overload. This will be accomplished using the frequently sampled intravenous glucose tolerance test (FSIVGTT) with insulin levels. Reversibility of the defect will be examined after subjects have undergone phlebotomy. The hypothesis will be verified in studies of isolated islets from mice carrying disrupted or mutant HFE genes. 3. Using animal models, determine if diabetes in hemochromatosis results only when insulin resistance is superimposed on an iron- mediated defect in insulin secretion. 4. Determine the sequence and relative contributions of insulin resistance and hepatic glucose production (HGP) in the evolution of diabetes in human hemochromatosis. Insulin resistance and HGP will be quantified by the hyperinsulinemic euglycemic clamp and stable isotope techniques in subjects with hemochromatosis who have normal or IGT, with or without hepatic involvement.